title: Calpain activation through galectin-3 inhibition sensitizes prostate cancer cells to cisplatin treatment.
abstract: Prostate cancer will develop chemoresistance following a period of chemotherapy. This is due, in part, to the acquisition of antiapoptotic properties by the cancer cells and, therefore, development of novel strategies for treatment is of critical need. Here, we attempt to clarify the role of the antiapoptotic molecule galectin-3 in prostate cancer cells using siRNA and antagonist approaches. The data showed that Gal-3 inhibition by siRNA or its antagonist GCS-100/modified citrus pectin (MCP) increased cisplatin-induced apoptosis of PC3 cells. Recent studies have indicated that cisplatin-induced apoptosis may be mediated by calpain, a calcium-dependent protease, as its activation leads to cleavage of androgen receptor into an androgen-independent isoform in prostate cancer cells. Thus, we examined whether calpain activation is associated with the Gal-3 function of regulating apoptosis. Here, we report that Gal-3 inhibition by siRNA or GCS-100/MCP enhances calpain activation, whereas Gal-3 overexpression inhibits it. Inhibition of calpain using its inhibitor and/or siRNA attenuated the proapoptotic effect of Gal-3 inhibition, suggesting that calpain activation may be a novel mechanism for the proapoptotic effect of Gal-3 inhibition. Thus, a paradigm shift for treating prostate cancer is suggested whereby a combination of a non-toxic anti-Gal-3 drug together with a toxic chemotherapeutic agent could serve as a novel therapeutic modality for chemoresistant prostate cancers.
authors.affiliation: Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: P
authors.initials: P
authors.lastname: Nangia-Makker
authors.forename: V
authors.initials: V
authors.lastname: Balan
authors.forename: V
authors.initials: V
authors.lastname: Hogan
authors.forename: A
authors.initials: A
authors.lastname: Raz
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002154:Calpain / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D037502:Galectin 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D011134:Polysaccharides / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C505531:GCS-100; D037502:Galectin 3; D011134:Polysaccharides; D034741:RNA, Small Interfering; D002154:Calpain; D002945:Cisplatin